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Multi-targeted anti-tumor activity evodiamine derivative and preparation method and application thereof

A technology of evodiamine and hydroxyevodiamine, which is applied in the field of medicine and can solve problems such as complex pharmacokinetic properties of drug-drug interactions

Pending Publication Date: 2019-07-30
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the clinical treatment of malignant tumors mainly adopts the combination drug method, but this method has many defects, such as the need to confirm the rationality of drug compatibility, possible drug-drug interactions and complex pharmacokinetic properties, etc.

Method used

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  • Multi-targeted anti-tumor activity evodiamine derivative and preparation method and application thereof
  • Multi-targeted anti-tumor activity evodiamine derivative and preparation method and application thereof
  • Multi-targeted anti-tumor activity evodiamine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] Preparation of 4-((3-fluoro-14-methyl-5-oxo-5,7,8,13,13b,14-hexahydro[2',3':3,4]pyrido[2,1- b] quinazolin-10-yl)oxy)-N-hydroxybutyramide (B13a)

[0119] (1) Preparation of intermediate B9: tert-butyl-3-fluoro-10-hydroxy-14-methyl-5-oxo-7,8,13b,14-tetrahydroindole[2',3':3 ,4]pyrido[2,1-b]quinazoline-13(5H) tert-butyl carboxylate

[0120] Put 500mg (1.48mmol) of 3-fluoro-10-hydroxyevodiamine (compound B8) and 0.97g (4.45mmol) of BOC anhydride in a 50mL flask, add 20mL of dry tetrahydrofuran to fully dissolve, and add 4-dimethyl Aminopyridine (DMAP) 18 mg (0.148 mmol), stirred and reacted at room temperature for 1 hour, and the reaction was monitored by silica gel thin-layer chromatography. After the reaction, evaporate to dryness under reduced pressure, add 20mL of methanol and mix well, take 1.1g of potassium carbonate and add it to the suspension, stir and react at room temperature for 3 hours, evaporate to dryness under reduced pressure again after the reaction, add ...

Embodiment 2

[0129] Preparation of N-(2-aminophenyl)-5-((3-fluoro-14-methyl-5-oxo-5,7,8,13,13b,14-hexahydro[2',3':3 ,4]pyrido[2,1-b]quinazol-10-yl)oxy)pentanamide (C11a)

[0130] (1) Preparation of intermediate C10a: 5-((3-fluoro-14-methyl-5-oxo 5,7,8,13,13b,14-hexahydro[2',3':3,4] Pyrido[2,1-b]quinazolin (10-yl)oxy)pentanoic acid

[0131] Weigh 0.1g of compound C8a and place it in a 25mL flask, add 10mL of prepared tetrahydrofuran:methanol:water=3:2:1 mixed solution to fully dissolve, slowly add 20mg hydrated lithium hydroxide under stirring, react at room temperature for 3 hours, and react After completion, evaporate to dryness under reduced pressure to remove the organic phase, slowly add dilute hydrochloric acid solution dropwise, adjust the pH of the solution to weak acidity, a yellow solid precipitates, filter under reduced pressure and dry the filter cake to obtain 90 mg of yellow solid with a yield of 93% . 1 H-NMR (DMSO-d 6 ,600MHz)δ:12.05(s,1H),10.98(s,1H),7.53(dd,J=3.1,8.9Hz...

Embodiment 3

[0136]Preparation of (E)-N-hydroxy-3-(4-((5-oxo-7,8,13,13b-tetrahydroindolo[2',3':3,4]pyrido[2, 1-b] quinazolin-14-(5H)-yl)methyl)phenyl)acrylamide (C8a)

[0137] Preparation of target product C8a

[0138] Add tryptamine (8.0g, 50mmol) and ethyl formate (23g) into a dry reaction flask, and heat to reflux at 80°C for 12 hours. Phosphorus oxychloride (12 mL) was slowly added dropwise under the conditions for 2 hours, and then the temperature was raised to room temperature to continue the reaction for 4 hours. After the reaction was complete, dichloromethane and unreacted phosphorus oxychloride were evaporated under reduced pressure, and the residue was washed with CH 3 COOH (200mL, 50%) was dissolved, then dissolved with NH 3 h 2 O to adjust the pH to 9-10, a yellow solid was precipitated, filtered under reduced pressure, washed the filter cake with water (2×30 mL), and dried to obtain the crude product C3. Take compound N-methylridine red acid anhydride (1.0g, 6.1mmol), K ...

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PUM

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Abstract

The invention belongs to the technical field of medicine, and provides a multi-targeted micromolecular anti-cancer drug based on topoisomerase 1 (Top1), topoisomerase 2 (Top2) and histone deacetylase(HDAC) and a preparation method of the multi-targeted micromolecular anti-cancer drug. The general molecular formulas of the compound are shown in the formulas I and II. Through pharmacological experiments, it is shown that the compound has high inhibitory activity to the topoisomerase 1, the topoisomerase 2 and the histone deacetylase, and has high in-vitro anti-tumor activity and excellent in-vivo anti-tumor effects. The invention further provides a preparation method of the derivative and application of the derivative in preparing a topoisomerase inhibitor, a histone deacetylase inhibitor and the anti-tumor drug.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an evodiamine derivative with multi-target anti-tumor activity and its preparation method and application. Background technique [0002] At present, cancer has become a disease that seriously threatens human health and life. At present, combination drugs are mainly used in clinical treatment of malignant tumors, but this method has many defects, such as the need to confirm the rationality of drug compatibility, possible drug-drug interactions, and complex pharmacokinetic properties. Multi-target drugs act on multiple key links or sites in the tumor disease network to exert a synergistic anti-tumor effect, and their therapeutic effect on tumors is better than that of a single drug. In addition, multi-target drugs have relatively simple absorption, distribution, metabolism and excretion processes, reduce the occurrence of drug-drug interactions, have lower side effects and better...

Claims

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Application Information

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IPC IPC(8): C07D471/14A61P35/00A61P35/02A61P5/00A61P37/02A61P25/00
CPCC07D471/14A61P35/00A61P35/02A61P5/00A61P37/02A61P25/00Y02P20/55
Inventor 董国强盛春泉陈树强鲁俊杰黄亚辉武善超李育
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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